We are analyzing the roles of genetic, immunologic and viral components in the etiology of auto-immune disease and malignant lymphomas that develop spontaneously in the New Zealand (NZB) mice. By making genetic crosses between NZB mice and "normal" virus-free mouse strains we have identified two autosomal dominant loci (Nzv-1 and Nzv-2) that determine infectious xenotropic virus expression in NZB mice. This genetic approach, together with improved virus assay techniques, have enabled us to segregate virus-inducing genes from genes determining autoimmunity and lymphoma development. We are presently developing congenic and recombinant inbred lines in order to isolate, map and study the mechanism of action of these genes. Basic defects of T and B lymphocyte function will also be analyzed by these genetic techniques and correlated with the development of disease. The genetic control of expression of another viral gene product, a glycoprotein (gp70) is also being analyzed in these crosses. gp70 expression is linked to normal differentiation of certain tissues in mice. Our preliminary results have shown that the abnormal expression of gp70 is another genetically prescribed defect in NZB mice and may be linked to increased incidence of malignant lymphomas. We are also doing experiments to test the hypothesis that the virologic and immunologic abnormalities in NZB mice are manifestations of a more fundamental defect of regulatory genes.